Obesity is a well known risk factor for the development of many very common diseases such as atherosclerosis, hypertension, type 2 diabetes (non-insulin dependent diabetes mellitus (NIDDM)), dyslipidaemia, coronary heart disease, and osteoarthritis and various malignancies. It also causes considerable problems through reduced motility and decreased quality of life. The incidence of obesity and thereby also these diseases is increasing throughout the entire industrialised world. Only a few pharmacological treatments are available to date, namely Sibutramine (acting via serotonergic and noradrenaline mechanisms, Abbott) and Orlistat (reducing fat uptake from the gut, Roche Pharm). However, due to the important effect of obesity as a risk factor in serious and even mortal and common diseases there is still a need for pharmaceutical compounds useful in the treatment of obesity.
The term obesity implies an excess of adipose tissue. In this context obesity is best viewed as any degree of excess adiposity that imparts a health risk. The distinction between normal and obese individuals can only be approximated, but the health risk imparted by obesity is probably a continuum with increasing adiposity. However, in the context of the present invention, individuals with a body mass index (BMI=body weight in kilograms divided by the square of the height in meters) above 25 are to be regarded as obese.
Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease and certain types of cancer. In the industrialized western world the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its treatment should be a high public health priority.
When energy intake exceeds energy expenditure, the excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity results, i.e. there are two components to weight balance, and an abnormality on either side (intake or expenditure) can lead to obesity.
Pro-opiomelanocortin (POMC) is the precursor for β-endorphin and melanocortin peptides, including melanocyte stimulating hormone (α-MSH) and adrenocorticotropin (ACTH). POMC is expressed in several peripheral and central tissues including melanocytes, pituitary and neurones of the hypothalamus. The POMC precursor is processed differently in different tissues resulting in the expression of different melanocortin peptides depending on the site of expression. In the anterior lobe of the pituitary, mainly ACTH is produced whereas in the intermediate lobe and the hypothalamic neurones the major peptides are α-MSH, β-MSH, desacetyl-α-MSH and β-endorphin. Several of the melanocortin peptides, including ACTH and α-MSH, have been demonstrated to have appetite suppressing activity when injected intracerebroventricular in rats (Vergoni et al, European Journal of Pharmacology 179, 347-355 (1990)). An appetite suppressing effect is also obtained with the artificial cyclic α-MSH analogue, MT-II disclosed in U.S. Pat. No. 5,731,408.
A family of five melanocortin receptor subtypes has been identified (melanocortin receptor 1-5, also called MC1, MC2, MC3, MC4 and MC5). The MC1, MC2 and MC5 are mainly expressed in peripheral tissues whereas MC3 and MC4 are mainly centrally expressed, however MC3 are also expressed in several peripheral tissues. MC3 receptors have besides being involved in energy homeostasis also been suggested to be involved in several inflammatory diseases. An MC3 agonist could have a positive effect on these diseases, e.g. gouty arthritis. MC5 receptors are mainly peripheral expressed and has been suggested to be involved in exocrine secretion and in inflammation. The MC4 receptor is shown to be involved in the regulation of body weight and feeding behaviour as MC4 knock out mice develop obesity (Huzar et al, Cell 88, 131-141 (1997)). Furthermore studies of either ectopic centrally expression of agouti (MC1, MC3 and MC4 antagonist) or over-expression of an endogenously occurring MC3 and MC4 antagonist (agouti gene related peptide, AGRP) in the brain demonstrated that the over-expression of these two antagonists lead to the development of obesity (Kleibig et al, PNAS 92, 4728-4732 (1995)). Furthermore icv injection of a C-terminal fragment of AGRP increases feeding and antagonises the inhibitory effect of α-MSH on food intake.
In humans several cases of families with obesity presumably due to frame shift mutations in the MC4 receptor have been described (e.g. Yeo et al, Nature Genetics 20, 111-112 (1998), Vaisse et al, Nature Genetics 20, 113-114).
In conclusion, a MC4 agonist could serve as an anorectic drug, and be useful in the treatment of obesity or obesity related diseases as well as in the treatment of other diseases, disorders or conditions, which are improved by activation of the MC4 receptor.
MC4 antagonists may be useful for treatment of cachaxia, anorexia, and for treatment of waisting in frail elderly patients. Furthermore, MC4 antagonists may be used for treatment of chronic pain, neuropathy and neurogenic inflammation.
A large number of patent applications disclose small molecules as melanocortin receptor modulators, examples of which are WO 03/009850, WO 03/007949 and WO 02/081443.
The use of peptides as melanocortin receptor modulators is also disclosed in a number of patents. EP 292291 discloses a number of 7 amino acid residues derivatives of α-MSH with increased potency characterized, e.g. by a D-Phe at position 7 in the α-MSH sequence and by the presence of a disulfide bridge.
U.S. Pat. No. 5,731,408 discloses cyclic peptides, seven amino in length having D-2-Nal at position 4, which are MC-4 antagonists.
U.S. Pat. No. 4,457,864 discloses trideca-peptide analogues of α-MSH, which display increased potency and prolongation. Preferred compounds have Nle and D-Phe in position 4 and 7, respectively.
WO 98/27113 discloses peptides with specific binding affinity for melanocortin receptors comprising the structure X—Y-His-B-Arg-Z, wherein X and Y are amino acid residues, Z is an aromatic amino acid residue and B is D-(2-thienyl)alanine or D-(3-pyridyl)alanine.
An MT-II analogue with the structure Ac-Nle-c[Asp-Hyp-D-Phe-Arg-Trp-Lys]-NH2 is disclosed in Proc. 2nd Inter. and 17th American Peptide Symp., Jun. 9-14, 2001, San Diego, 992, 893; an MT-II analogue with the structure Ac-Nle-c[Asp-Ala-D-Phe-Arg-Trp-Lys]-NH2 is disclosed in Peptides, 20(3), 1999, 401-409; an MT-II analogue with the structure Ac-Nle-c[Asp-Gln-D-Phe-Arg-Trp-Lys]-NH2 is disclosed in Bioorg. Med. Chem. Lett, 13(7), 2003, 1307-1311; the two MT-II analogues Ac-Nle-c[Asp-Glu-D-Phe-Arg-Trp-Lys]-NH2 and Ac-Nle-c[Asp-Lys-D-Phe-Arg-Trp-Lys]-NH2 are disclosed in Biochem. Res. Commun., 272(1), 2000, 23-28; and an MT-II analogue Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-NH2 is mentioned in J. Peptide Res., 62, 2003, 199-206.
It remains a challenge to provide melanocortin receptor modifiers which are highly potent and which have a suitable solubility and thus bioavailability in combination with an appropriate selectivity.